研究首度發現dehydrocostuslactone (DHE)對乳癌細胞株MCF-7和MDA-MB-231細胞的抗癌活性，並深入探討其作用之相關機制。DHE可藉由終止細胞週期的演進使MCF-7停滯於G0/G1-S期和MDA-MB-231停滯於S-G2/M期，並誘導細胞進行細胞凋亡而能有效的抑制細胞的生長。在細胞週期調控方面，DHE可增加MCF-7細胞株之p53和p21的表現，並且降低cyclin D1、cyclin D2、cdk2、cdk 4和cdc25A的蛋白總量，而使細胞週期停滯於G0/G1-S。相對的DHE也會在MDA-MB-231細胞減少cyclin A和cyclin B的表現，以及透過Chk1活化而增加cdc2和cdc25C的磷酸化，最後使MDA-MB-231細胞週期停滯於S-G2/M期。在細胞凋亡方面，DHE誘導細胞走向細胞凋亡是透過caspases-independent pathway。將細胞事先用pan-caspase抑制劑處理並不能影響DHE所造成的細胞增生抑制現象。另外，DHE會造成apoptosis inducing factor (AIF)和endonuclease G (Endo G)由粒線體轉位到細胞核，因而導致DNA的裂解。我們也發現DHE能藉由阻斷janus tyrosine kinases (JAK)，以及它下游分子signal transducers and activators of transcription 3 (STAT3)的磷酸化作用，來抑制細胞存活訊息JAK/STAT3訊息傳遞路徑。此外，在兩株乳癌細胞中經由藥物DHE處理後可抑制STAT3的核轉位及與DNA的結合能力。而suppressor of cytokine signaling-1 (SOCS-1) 和suppressor of cytokine signaling-3 (SOCS-3)的表現增加是與阻斷JAK/STAT3活化具有相關性的。綜合以上，這些結果證實JAK/STAT3的抑制在DHE所誘導人類乳癌細胞週期停滯及細胞凋亡扮演著關鍵的角色。研究首度發現dehydrocostuslactone (DHE)對乳癌細胞株... This study is the first to investigate the anticancer effect of DHE in human breast cancer cells. DHE exhibited cell proliferation inhibition by inducing cells to undergo G2/M arrest and apoptotic death. DHE treatment blocked the progression of cell cycle at G0/G1-S phase in MCF-7, but at S-G2/M phase in MDA-MB-231 cells. Blockade of the cell cycle at G0/G1-S in MCF-7 was associated with increased p53 and p21, and reduced amounts of cyclin D1, cyclin D2, cdk2 and cdk 4. In contrast, DHE caused S-G2/M phase arrest by decreasing the expression of cyclin A and cyclin B, and increasing the levels of inactivated phospho-Cdc2 and phospho-Cdc25C by Chk1 activation. DHE induced apoptosis through caspases-independent pathway. Pretreatment of cells with pan-caspase inhibitor failed to affect DHE-mediated cell death. In addition, DHE increased the translocation of apoptosis inducing factor (AIF) and endonuclease G (Endo G) from mitochondria to nuclei, resulting in DNA fragmentation. We also found that DHE inhibited survival signaling through the janus tyrosine kinases (JAK)/signal transducers and activators of transcription 3 (STAT3) signaling pathway by blocking the phosphorylation of JAK and its downstream targets STAT3. Furthermore, nuclei translocation and DNA binding activity of STAT3 were also inhibited by DHE treatment in both cancer cell lines. Blockade of the activation of JAK/STAT3 was associated with increased suppressor of cytokine signaling-1 and -3 (SOCS-1 and -3) expression. Taken together, these results imply a critical role for JAK/STAT3 inhibition in DHE-induced cell cycle arrest and apoptosis of human breast cancer cells.
